In advanced stages of Parkinson's disease (PD), the absence of spontaneous volitional movements (akinesia) often becomes the most debilitating aspect of the disease. In a subset of patients, akinesia manifests as an episodic impairment in the initiation of gait (start hesitation) in conjunction with freezing of gait (FOG). With disease progression, akinesia, start hesitation and FOG often becomes refractory to current treatments such as levodopa and deep brain stimulation. Currently there are no effective treatments for these symptoms. Yet, one of the paradoxes of PD is it that, under certain contexts, the provision of external cues can markedly facilitate movement initiation, even in those with profound akinesia in the off medication state. This observation demonstrates that patients with PD retain the capacity to initiate movement, but for reasons that are not understood, are unable to reliably access these pathways, particularly in self-initiated (non-cued) conditions. Despite the consensus that external cues can facilitate movement initiation in PD, clinical trials examining the efficacy of using external cues in the home environment have been disappointing. We propose that the utility of using external cues in clinical and home environments is currently limited by our lack of understanding of the conditions required to reliably facilitate initiation with cues and the mechanisms mediating the release of movement. The first Specific Aim of this project will examine the effects of cueing modality (acoustic, visual or somatosensory) and cue timing on the preparation and initiation of gait in patients with start hesitation. Information derived from these experiments can be used to establish stimulus presentation protocols that can be implemented in the clinical or home environments or via portable devices. Specific Aim 2 will use high- resolution EEG recordings and functional magnetic resonance imaging (fMRI) to examine the cortical and subcortical structures that mediate the preparation and release of movements by external cues. Specific Aim 3 will use transcranial direct current stimulation (tDCS) to examine the effects of transient suppression or facilitation of frontal cortical structures that are considered to a play role in the planning, preparation and initiation of gait and upper limb movements. These experiments will provide insight into the mechanisms and pathways that enable external cues to circumvent the impaired initiation of voluntary movements in patients with PD, such as start hesitation, and will provide an empirical rationale for the development of novel therapeutic interventions that facilitate these pathways. PUBLIC HEALTH RELEVANCE: In a large subset of patients with Parkinson's disease, one of the most disabling aspect of their disorder is a syndrome characterized by episodic impairments in the initiation of gait (termed start hesitation) in conjunction with freezing of gait (FOG). Currently there are no effective treatments for these symptoms. Yet, it is well known that under certain contexts, the provision of external cues can markedly facilitate gait initiation. This project will investigate the optimal strategies for cueing movement initiation to improve the efficacy and reliability of cueing in clinical and home settings and to develop standardized cueing protocols for portable devices. In addition, we will examine the mechanisms and pathways that enable external cues to circumvent impaired gait initiation with the goal to develop novel therapeutic interventions that facilitate these pathways.